The photoreceptor cells of the retina carry out the essential task of translating light into electrical signals that can be passed on and analyzed by the rest of the visual system. Diseases that cause the photoreceptor cells to degenerate lead to irreversible blindness, because the remaining neurons of the retina are not sensitive to light and therefore cannot substitute for the loss of the photoreceptor cells. The goal of the proposed research is to induce sensitivity to light in the surviving retinal bipolar neurons, which would normally receive synaptic inputs from photoreceptors, as a strategy to restore useful vision after photoreceptor degeneration. The approach is to use genetic engineering to induce bipolar neurons to express two different light-activated ion channels, channelrhodopsin-2 and halorhodopsin, that will mimic the naturally occurring light response of ON and OFF bipolar cells, respectively. To drive expression in bipolar neurons, the project will make use of transgenic animals that incorporate DNA encoding channelrhodopsin-2 or halorhodopsin under the control of gene regulatory elements that will confer expression selectively in each of the two subtypes of bipolar neurons. The results will establish the feasibility of using these genetically encoded photosensor proteins as a functional replacement for missing photoreceptors in the diseased retina. PUBLIC HEALTH RELEVANCE: Degeneration of the photoreceptor cells in the retina is a leading cause of blindness, and at present, there is no treatment. The proposed research explores a new approach for restoration of vision despite the loss of photoreceptor cells. The strategy uses molecular engineering to make the remaining neurons of the retina sensitive to light, thereby replacing the function of the missing photoreceptors.